Patent GB-1502328-A (GB)
Title: Prostaglandin derivatives
IPC: C07F9/40
Filed: 1975-06-18
Abstract: 1502328 11-Deoxyprostaglandins AMERICAN HOME PRODUCTS CORP 18 June 1975 [19 June 1974] 25892/75 Heading C2C [Also in Division C3]  The invention comprises processes for preparing 11-deoxyprostaglandins of the Formula II wherein R<SP>2</SP> is H; R<SP>4</SP>, R<SP>5</SP>, R<SP>6</SP> and R<SP>7</SP> each are H or C 1-3  alkyl; X is OH and Y is H or X and Y together are oxo; Z is -CH 2 CH 2 - or trans- -CH=CH-; m is 1 to 3 and n is 2 to 5 with the proviso that at least one of R<SP>4</SP>, R<SP>5</SP> and R<SP>6</SP> is H and pharmaceutically acceptable salts of the compounds in which R<SP>7</SP> is H, by reducing compounds of the Formula 4 wherein R<SP>2</SP> is H and R<SP>6</SP> is C 1-6  alkyl or R<SP>2</SP> is hydroxy protecting group and R<SP>6</SP> is H, with complex borohydrides to obtain mixtures of lactones of the Formula 6 and acids of the Formula 5 and, if desired, transforming the acids of Formula 5 to lactones of the Formula 6 by treatment with methane-sulphonyl or p-toluenesulphonyl chloride or bromide and, if desired, removing protecting group R<SP>2</SP>, subjecting lactones of Formula 6: (i) where R<SP>2</SP> is H, R<SP>6</SP> is H, to oxidation to give lactones of the Formula 7 or (ii) where R<SP>6</SP> is H to catalytic reduction to give corresponding dihydrolactones; or (iii) to reduction with a monoalkyl or dialkyl aluminium hydride to give the corresponding lactols and then (A) catalytically reducing lactones of Formula 7 above to give the corresponding dihydrolactones, reducing the latter compounds with metal borohydride to give lactones of the Formula 9 where R<SP>2</SP> and R<SP>6</SP> are H, followed by optionally protecting hydroxy group, reducing the lactones of Formula 9 to the corresponding lactols and condensing the latter compound with Wittig reagents of the formula in which Hal is Cl, Br or I to give compounds of Formula 11 above in which R<SP>6</SP> is H; γ is OH; Y is 11 and Z is -CH 2 CH 2 - and removing protecting groups from those compounds in which R<SP>2</SP> is a hydroxy protecting group; or (B) catalytically reducing lactones of Formula 7 above in which R<SP>4</SP> is H to obtain the corresponding dihydrolactones, reacting the latter with C 1-3  alkyl-magnesium halides to obtain lactones of Formula 9 above in which R<SP>2</SP> and R<SP>4</SP> are H and R<SP>3</SP> is C 1-3  alkyl, reducing the lastnamed compound and treating the resulting lactols with Wittig reagents of the above formula to give the corresponding compounds of Formula 11 in which R<SP>2</SP> and R<SP>4</SP> are H, R<SP>6</SP> is C 1-3  alkyl, X is OH, Y is H and Z is -CH 2 CH 2 ; or (C) reacting lactones of Formula 7 in which R<SP>4</SP> is H with C 1-3  alkylmagnesium halides, reducing the resulting lactones and reacting the lactols thus obtained with Wittig reagents of the above formula to give the corresponding compounds of Formula 11 in which R<SP>2</SP> and R<SP>4</SP> are H, R<SP>8</SP> is C 1-6  alkyl, X is OH, Y is H and Z is trans-CH = CH; or (D) transforming the lactones of Formula 9 in which R<SP>2</SP> is H or hydroxy protecting group and R<SP>6</SP> is H to the corresponding compound of Formula 11 in which Z is CH 2 CH 2 , R<SP>2</SP> is H or a hydroxy protecting group, R<SP>6</SP> is H, Y is OH and Y is H, as described under (A); (E) treating lactols of the Formula 13 with Wittig reagents of the above formula, to obtain a compound of Formula 11 in which X is OH, Y is H and Z is trans-CH=CH 2 ; and removing protecting group, if present; and after processes A, B, C, D or E, if desired, oxidizing the resulting compounds of Formula 11 and, if necessary, removing protecting groups R<SP>2</SP>. Any resulting acids may be converted into C 1-3  alkyl esters or salts. The invention also comprises 9,15 - dihydroxy - 15 - methyl - cis- 5 - prostenoic acid, 9,15 - dihydroxy - 16,16- dimethyl - cis - 5 - prostenoic acid, 15 - hydroxy - 16,16 - dimethyl - 9 - oxo - cis - 5- prostenoic acid, and 15-hydroxy-15-methyl-9- oxo-cis-5-prostenoic acid and pharmaceutically acceptable salts thereof, and racemates of methyl 15 - hydroxy - 16,16 - dimethyl - 9 - oxocis-5-prostenoate having Rf's of 0À47 and 0À37 on thin layer plates of silica gel when using ethyl acetate-benzene (1 : 4 v./v.) as the mobile phase. The following intermediates are also prepared: 4 - [3 - (2 - tetrahydropyranyloxy) - 3 - methyltrans - 1 - octenyl] - hexahydro - 2H - cyclopenta[b]furan - 2 - ol, and 4 - (3 - hydroxy - 3- methyloctyl) - hexahydro - 2H - cyclopenta[b]- furan-2-ol. Pharmaceutical compositions, suitable for oral or parenteral administration, contain the above 11-deoxyprostaglandins and suitable carriers. The compounds possess similar pharmacological properties to the naturally occurring prostaglandins. Reference has been directed by the Comptroller to Specifications 1,355,993, 1,406,621, 1,422,319, 1,434,620, 1,438,130, 1,444,963, 1,445,628 and 1,445,630.